A patient you are admitting to the hospital tells you that he is in a clinical trial. A close friend is a participant in a clinical trial and tells you that she’s not sure she understands what the study is about. Your neighbor has cancer and wants to locate a clinical trial, but tells you she doesn’t want to be a “guinea pig.” Each year in the United States, thousands of people are subjects in clinical trials, and millions of Americans follow the results of research in the media. Do you know how to respond to questions that your patients, friends, and neighbors might ask? Read on to find some answers.

From lab to prescription pad

A clinical trial is a research study involving human participants whose purpose is to answer specific health questions about how to cure or control disease and how to enhance health. Clinical trials are sponsored and funded by a number of organizations, such as medical institutions, foundations, and pharmaceutical companies, as well as government agencies, such as the National Institutes of Health, the Department of Defense, and the Department of Veterans Affairs.¹ Clinical trials are conducted in hospitals, universities, physician offices, and community clinics. There are several types of clinical trials. Treatment trials test experimental treatments, new drug combinations, or new approaches to surgery or radiation therapy. Prevention trials, often conducted over long-time periods, study how to prevent disease or how to prevent disease from recurring. These types of studies may involve drugs, vitamins and minerals, vaccines, or lifestyle changes.¹ Quality of life or supportive care trials evaluate ways to improve comfort and quality of life for those with a chronic illness and their families.^1,2

Many clinical trials are aimed at new drug development. The process of developing a new drug that will be both safe and effective often takes years and is an enormous financial investment.² Once a promising compound has been identified and has completed initial testing in the laboratory, the company developing the drug files an application with the U.S. Food and Drug Administration (www.fda.gov) for an investigational new drug number. The application gives the FDA information supporting the hypothesis that it is reasonable to begin testing with human subjects.^1,2 Clinical trials occur in four phases, with each addressing specific questions:^1,2

• Phase 1 — Is the treatment safe?
• Phase 2 — Does the treatment work?
• Phase 3 — How does this treatment compare with existing treatments?
• Phase 4 — Are there other potential uses for this treatment, and what are the long-term adverse effects?

A Phase I trial tests a drug or device for the first time in a small number of humans. The effective dose of the drug and adverse effects in humans are not known. The purpose of a Phase I trial is to determine the safe dose of a drug, to assess adverse effects, and to study how the drug is metabolized.² To answer these questions, a few study participants are given the study dose determined from the preclinical animal trials. If they complete a drug cycle without unacceptable adverse effects, the dose of the drug is increased.² A few more participants are enrolled and take the drug at a higher dose. Dose escalation continues until one of the participants experiences an unacceptable adverse effect.² Phase I trials are always single-agent studies — only the study drug is given to patients. Those enrolled in a Phase 1 study may have exhausted all types of standard therapy and may not be eligible for other studies.²

A Phase 2 trial determines the drug’s efficacy — its ability to relieve symptoms or stop the progression of disease in about 100 to 300 people.¹ All participants receive the study drug at the same dose and on the same schedule. If a drug appears promising based on participants’ response rate and the duration of the response, further development may be pursued in a Phase 3 trial. Phase 3 trials are usually large, multicenter studies that involve thousands of people. Phase 3 trials compare the proposed treatment with at least one other existing effective therapy. Each treatment tested in the trial is called a study arm.² Participants are assigned to a specific arm of the study by randomization — a process often described to those participating as being like “the flip of a coin.” In a randomized study, the experimental therapy is known as the treatment arm. The treatment that is not part of the drug being tested is called the control arm. To prevent researcher bias, some randomized studies are double-blinded — neither the research team nor the subject knows what treatment the subject is receiving. Phase 4 trials are done after a drug has received FDA approval and is commercially available. This phase assesses other uses for the drug, known as off-label uses, and further evaluates adverse effects.^1,2 Before the FDA approves a drug as safe, it’s tested on several thousand people, a sample size usually large enough to identify serious adverse effects. However, when drugs are used commercially by millions, rare but potentially lethal consequences can occur. Safety concerns related to popular anti-inflammatory drugs, such as refocoxib (Vioxx) and celecoxib (Celebrex) prompted the FDA to announce a plan to strengthen its post-marketing drug safety program.¹

Clinical trials are conducted in a specific way. Each study protocol includes a background statement of the health problem and its significance, a hypothesis proposing how the drug or device will solve the problem, the study design and procedures, inclusion and exclusion criteria, and potential benefits and risks, including adverse effects. Inclusion criteria are the factors that allow someone to participate in a clinical trial; factors that eliminate someone from participating are exclusion criteria.^1,2 Inclusion and exclusion criteria may include factors such as age, gender, the type and stage of a disease, the patient’s previous treatment history, and other medical conditions.² Defining inclusion and exclusion criteria helps the study produce reliable results.^1,2 In some situations, patients don’t qualify for a clinical trial but may benefit from using the drug being studied. An FDA process known as expanded access allows drug manufacturers to provide the experimental drug to people with a life-threatening or serious illness for which there is no alternative treatment.¹ The principal investigator (PI) is the leader of the research team; he or she is responsible for conducting the clinical trial following good clinical practice guidelines. A study coordinator or clinical research coordinator handles all the details of the study. Nurses have an excellent background for working in research and often serve as study coordinators.² Nurses interested in this field should contact the Association of Clinical Research Professionals (acrpnet.org), an international organization that provides educational, certification, and networking opportunities for research professionals. The designation CCRC indicates a person is a certified clinical research coordinator.

The research team assesses the health status of each participant at the beginning of the trial; gives specific instructions for participating in the trial; monitors the participant carefully during the trial; ensures informed consent; reports to the FDA, pharmaceutical companies, and institutional review boards (IRBs) (www.fda.gov/oc/ohrt/irbs); and continues to follow the person after the trial is completed.

To participate or not

People should carefully consider the advantages and disadvantages of enrolling in a clinical trial. On the plus side, participation in a clinical trial allows individuals to play an active role in their own health care, and if a person is assigned to the experimental or treatment arm of the study, he or she may receive a treatment that is more effective than current therapy.^1,2 People involved in clinical trials also have access to expert medical care at leading medical facilities and receive more intense monitoring than they would if they were receiving a similar standard of care therapy. Some people participate in clinical trials because doing so may help future patients. Participants must also weigh the disadvantages of participation. Although an experimental treatment has been tested in the laboratory and in animal studies, there may be unknown adverse effects, ranging from unpleasant symptoms to potentially life-threatening adverse effects.² In addition, a participant may be randomized to the control arm of the study and thus receive no additional therapeutic benefit. Alternatively, the study treatment may not be effective. Following the research protocol usually requires more time and attention than customary treatment, including trips to the research study site, physician visits, laboratory and radiological tests, complex dosing regimens, and, in some instances, hospital stays.^1,2 Clinical trials may not cover the costs of medical care involved, and there may also be insurance copayments or deductibles that an individual participant may be responsible for.^1,2

Protecting participants

Today there are a number of safeguards to protect the rights of people who participate in research. These safeguards arose out of significant human rights abuses. In the United States, the abuses that were part of the Tuskegee Syphilis Study (www.cdc.gov/nchstp/od/tuskegee/time.htm) resulted in dramatic changes in the protection of human subjects. As a result of the abuses, great effort was devoted to ensure that people who were part of any investigational treatment had their rights as human subjects protected. At the end of World War II, the Nuremberg Code was adopted as an internationally recognized code of research ethics.^1,2 The Declaration of Helsinki (http://ohsr.od.nih.gov/guidelines/helsinki.html), issued in 1961, is also internationally recognized as a worldwide standard for the conduct of clinical trials.² During his presidency, John F. Kennedy approved a Consumer Bill of Rights, and in many states, a Patient’s Bill of Rights is attached to each research consent form. In 1974, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was established. The commission’s findings and recommendations were published in 1978 in the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects² (www.nihtraining.com/ohsrsite/guidelines/belmont.html). All research supported by the U.S. government adheres to the ethical principles of respect for persons, beneficence, and justice.² Respect for persons acknowledges the dignity and freedom of each individual and requires that research subjects give informed consent before participating in a clinical trial. Beneficence requires that researchers maximize benefit and minimize risks and aim for a reasonable balance between risks and benefits. Justice requires that the selection and recruitment of research subjects are equitable and that vulnerable populations, such as children and the developmentally disabled, are protected.

As a result of federal regulations, all studies involving human subjects in the United States must be reviewed and approved by an IRB. An IRB consists of people with varying backgrounds, such as physicians, research scientists, pharmacists, nurses, and social workers. At least one member of the IRB must not be affiliated with the research institution.^1,2 The IRB is charged with several important responsibilities:

1. To assess that risks to participants are minimized and are reasonable in relation to potential benefits and new knowledge
2. To ensure that informed consent is obtained
3. To evaluate that patient selection is fair and that safeguards are in place to protect vulnerable populations
4. To determine that subjects’ privacy is protected. Even after a study is approved and begun, the IRB monitors the ongoing clinical trial. Every serious adverse event that a participant experiences after enrolling in a clinical trial must be reported to the IRB and to government agencies.^1,2

Subjects really informed?

Before deciding whether to participate in a clinical trial, people should know as much as they possibly can about the trial and have the opportunity to have their questions answered. Research subjects should know:^1,2

• Why the study is being done.
• Who is conducting the study.
• Who is going to be in the study.
• Why researchers believe the new treatment being tested may be effective.
• What kinds of tests and treatments are involved.
• How the possible risks, adverse effects, and benefits of the study compare with current treatment.
• What the alternatives are to participation.
• How long the study will last.
• Who will pay for the study.
• What type of long-term follow-up care is needed.
• How participants will learn about the results of the study.
• Who is in charge of participants’ care and who should be contacted for questions, problems, or concerns.

Study participants must be informed that participation in a clinical trial is voluntary and that they have the right to withdraw from the trial at any time without jeopardizing their rights to future care. Informed consent is a key to ethical research and is required by federal law. Informed consent involves more than disclosing the required legal elements. A valid informed consent requires that research participants truly understand the elements of the clinical trial.³ The most important aspect of the research consent is that it be written (or read to the subject or the subject’s representative) in a language the subject understands. This is a formidable challenge because an informed consent for a clinical trial contains highly complex information. Obtaining consent for participation in research is particularly challenging because it requires a level of comprehension beyond that required for consent for customary medical care.⁴ A large body of literature indicates that most Americans do not understand the language used in informed-consent forms.^4,5 One study showed that approximately 30% of subjects in a cross-section of oncology clinical trials believed that their treatment had already been proven to be the best treatment for their cancer.⁵

Nearly half of all Americans read at or below the eighth-grade level.⁴ Lower educational level, mental illness, and, in some instances, advanced age are associated with less understanding.³ Readability indices can be used to evaluate the grade level at which written materials are produced. The Flesch-Kincaid readability scale is automated in Microsoft Word. This scale assesses readability on the basis of the average number of syllables per word and the average number of words per sentence.⁴ According to the National Cancer Institute, research consents should be written between the sixth- and eighth-grade levels.⁶ Here are two examples of consent information about voluntary participation, the first written at the sixth-grade level and the second at the 12th-grade level:

• Taking part in this study is your choice. If you decide not to take part, this will not harm relations with your health care providers.
• Your participation in this study is strictly voluntary. You have the right to choose not to participate or to withdraw your participation at any point in this study without prejudice to your future health care or to other services to which you are otherwise entitled.⁶

Determining how to improve research consent comprehension is a national concern. One study showed that having a study team member or an educator spend more time talking one-to-one with a potential study participant may be the most effective way to ensure that participants really comprehend what they are consenting to.⁵ An extended personal discussion promotes more active engagement and responsiveness to individual needs than more passive strategies, such as a media presentation or a more detailed written consent form. This recommendation also underscores the premise that informed consent is more than just the action of reading a form and signing it.

What about the newly admitted patient who tells you he is involved in a clinical trial? In this situation, the goal is to protect the patient by procedures that ensure his safety and that also promote his continuing participation in the clinical trial while he is hospitalized. Make sure that your agency has policies and procedures in place that address the following questions: Does the patient’s primary provider know the patient is in a clinical trial? Where is the research protocol located? Do you know the adverse effects of the investigational drug? What help does your pharmacy provide in educating you about the investigational drug and its potential adverse effects? Who administers the drug — you or the patient? Was this admission due to an adverse event?

Tell your friend who needs more information about the study she is in to contact the PI with her questions. If after that conversation she still has questions, she should contact the chair of the IRB that approved the protocol. The names and contact numbers of both of these people are found on her copy of the consent. Advise your neighbor who wants to find a clinical trial to access www.clinicaltrials.gov, and tell her about the safeguards in place to protect her rights. As patient advocates, nurses have an ethical responsibility to advise people about their rights when they participate in clinical trials. Whether in the work setting or in the community, nurses can serve as valuable resources for information about clinical trials.